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In vivo cerebrovascular imaging with fluorescently-tagged magnetic protein nanoparticles (f-MPNPs) enhances microvascular contrast for simultaneous visualization by whole-brain time-of-flight MRI angiography and high resolution fluorescence imaging.

The Slyne Basin, located offshore NW Ireland, is a narrow and elongated basin composed of a series of interconnected grabens and half-grabens, separated by transfer zones coincident with deep crustal structures formed during the Silurian- to Devonian-aged Caledonian Orogeny. The basin is the product of a complex, polyphase structural evolution stretching from the Permian to the Miocene. Initially, relatively low-strain rifting occurred in the Late Permian and again in the latest Triassic to Middle Jurassic, followed by a third phase of high-strain rifting during the Late Jurassic. These extensional events were punctuated by periods of tectonic quiescence during the Early Triassic and Middle Jurassic. Late Jurassic strain was primarily accommodated by several kilometres of slip on the basin-bounding faults, which formed through the breaching of relay ramps between left-stepping fault segments developed during earlier Permian and Early–Middle Jurassic rift phases. Following the cessation of rifting at the end of the Jurassic, the area experienced kilometre-scale uplift and erosion during the Early Cretaceous and a second, less severe phase of denudation during the Palaeocene. These post-rift events formed distinct regional post-rift unconformities and resulted in a reduced post-rift sedimentary section. The structural evolution of the Slyne Basin was influenced by pre-existing Caledonian structures at a high angle to the basinal trend. The basin illustrates a rarely documented style of fault reactivation in which basin-bounding faults are oblique to the earlier structural trend, but the initial fault segments are parallel to this trend. The result is a reversal of the sense of stepping of the initial fault segments generally associated with basement control on basin-bounding faults.

Faults and fractures are a critical store and pathway for groundwater in Ireland’s limestone bedrock aquifers either directly as conductive structures or indirectly as the locus for the development of karst conduits. From the quantitative analysis of post-Devonian faults and fractures in a range of lithological sequences, this report describes the principal characteristics of Cenozoic strike-slip faults and joints, the youngest and the most intrinsically conductive fractures within Irish bedrock. Analysis of these structures in more than 120 outcrop, quarry, mine and cave locations in a range of bedrock types, provides a basis for: (1) definition of quantitative models for their depth dependency, lithological control, scaling systematics and links to preexisting structure, (2) conceptualisation of their impact on groundwater behaviour, and (3) estimation of groundwater flow parameters. The quantitative models provide constraints on fracture-controlled flow connectivity. Commonly observed decreases in sustainable flows and water strike interceptions with depth are attributed to increasing confinement and decreasing fracture connectivity and dissolution. Faults and joints have quite different end member geometries, with faults having strongly heterogeneous scale-independent properties and joints more often showing scale-dependent stratabound properties. The highest and most sustainable groundwater flows are usually associated with the complexity of structure of Cenozoic faults and of preexisting Carboniferous structures (on which conductive fracturing localises), enhanced by karstification and strongly jointed limestone bedrock particularly in the near-surface. Increased groundwater flow is promoted within bedded, rather than massive (i.e. unbedded), limestone sequences, characterised by bedding-parallel fractures and karst connecting otherwise subvertical fractures and subvertical wells.

A hydrogeological conceptual model of the source, circulation pathways and temporal variation of a low-enthalpy thermal spring in a fractured limestone setting is derived from a multidisciplinary approach. St. Gorman's Well is a thermal spring in east-central Ireland with a complex and variable temperature profile (maximum of 21.8 °C). Geophysical data from a three-dimensional(3D)audio-magnetotelluric(AMT) survey are combined with time-lapse hydrogeological data and information from a previously published hydrochemical analysis to investigate the operation of this intriguing hydrothermal system. Hydrochemical analysis and time-lapse measurements suggest that the thermal waters flow within the fractured limestones of the Carboniferous Dublin Basin at all times but display variability in discharge and temperature. The 3D electrical resistivity model of the subsurface revealed two prominent structures: (1) a NW-aligned faulted contact between two limestone lithologies; and (2) a dissolutionally enhanced, N-aligned, fault of probable Cenozoic age. The intersection of these two structures, which has allowed for karstification of the limestone bedrock, has created conduits facilitating the operation of relatively deep hydrothermal circulation (likely estimated depths between 240 and 1,000 m) within the limestone succession of the Dublin Basin. The results of this study support a hypothesis that the maximum temperature and simultaneous increased discharge observed at St. Gorman's Well each winter is the result of rapid infiltration, heating and recirculation of meteoric waters within a structurally controlled hydrothermal circulation system.The online version contains supplementary material available at 10.1007/s10040-021-02393-1.Un modèle conceptuel hydrogéologique de la source, des voies de circulation et de la variation temporelle d’une source thermale à faible enthalpie dans un contexte de calcaire fracturé est dérivé d’une approche multidisciplinaire. St. Gorman’s Well est une source thermale du centre-est de l’Irlande avec un profil de température complexe et variable (maximum de 21.8 °C). Les données géophysiques d’un levé audio-magnétotellurique (AMT) en trois dimensions (3D) sont combinées avec des données hydrogéologiques à intervalles de temps et des informations provenant d’une analyse hydrochimique publiée précédemment pour étudier le fonctionnement de cet intrigant système hydrothermal. L’analyse hydrochimique et les mesures à différentes périodes suggèrent que les eaux thermales s’écoulent à tout moment dans les calcaires fracturés du bassin carbonifère de Dublin, mais présentent une variabilité de débit et de température. Le modèle de résistivité électrique 3D du sous-sol a révélé deux structures importantes: (1) un contact faillé orienté NW entre deux lithologies calcaires; et (2) une faille alignée au Nord, améliorée par dissolution, d’âge cénozoïque probable. L’intersection de ces deux structures, qui a permis la karstification du socle calcaire, a créé des conduits facilitant le fonctionnement d’une circulation hydrothermale relativement profonde (profondeurs estimées vraisemblablement entre 240 et 1,000 m) au sein de la succession calcaire du bassin de Dublin. Les résultats de cette étude appuient l’hypothèse selon laquelle la température maximale et l’augmentation simultanée du débit observés à St. Gorman’s Well chaque hiver sont le résultat d’une infiltration, d’un réchauffement et d’une recirculation rapides des eaux météoriques dans un système de circulation hydrothermale structurellement contrôlé.Se deriva un modelo conceptual hidrogeológico de la fuente, las vías de circulación y la variación temporal de un manantial termal de baja entalpía en un entorno de caliza fracturada a partir de un enfoque multidisciplinar. Gorman’s Well es un manantial termal en el centro-este de Irlanda con un perfil de temperatura complejo y variable (máximo de 21.8 °C). Los datos geofísicos de un estudio audio-magnetotelúrico (AMT) tridimensional (3D) se combinan con los datos hidrogeológicos de un lapso de tiempo y la información de un análisis hidroquímico previamente publicado para investigar el funcionamiento de este intrigante sistema hidrotermal. El análisis hidroquímico y las mediciones a intervalos de tiempo sugieren que las aguas termales fluyen dentro de las calizas fracturadas de la cuenca carbonífera de Dublín en todo momento, pero muestran variabilidad en la descarga y la temperatura. El modelo de resistividad eléctrica tridimensional del subsuelo reveló dos estructuras prominentes: (1) un contacto de falla alineado al NW entre dos litologías calcáreas; y (2) una falla de disolución incrementada, alineada al N, de probable edad cenozoica. La intersección de estas dos estructuras, que ha permitido la karstificación del lecho rocoso calcáreo, ha creado conductos que facilitan el funcionamiento de una circulación hidrotermal relativamente profunda (probablemente a profundidades estimadas entre 240 y 1,000 m) dentro de la sucesión calcárea de la cuenca de Dublín. Los resultados de este estudio apoyan la hipótesis de que la temperatura máxima y el aumento simultáneo de la descarga observados en St. Gorman’s Well cada invierno son el resultado de una rápida infiltración, calentamiento y recirculación de aguas meteóricas dentro de un sistema de circulación hidrotermal estructuralmente controlado.通过多学科方法, 建立了裂缝型石灰岩环境中低焓温泉的来源、循环路径和时间变化的水文地质概念模型。圣戈尔曼井是爱尔兰中东部的温泉, 温度分布复杂多变 (最高21.8 °C)。将三维 (3D) 音频-大地电磁 (AMT) 调查的地球物理数据与延时水文地质数据和先前发布的水化学分析信息相结合, 调查了有趣的热液系统运行情况。水化学分析和延时测量表明, 热水一直在石炭系都柏林盆地的裂缝型石灰岩内流动, 但流量和温度有变异性。地下的 3D 电阻率模型揭示了两个突出的结构:(1) 两个石灰岩岩性之间的 NW 向断层接触; 和 (2) 可能新生代的溶蚀增强的和N向的断层。两个结构的交叉点使石灰岩基岩发生岩溶作用, 形成了通道, 促进了都柏林盆地石灰岩序列内相对较深的热液循环 (估计深度可能在 240 至 1,000 m 之间)作用。通过这项研究发现每年冬天在圣戈尔曼井观察到的最高温度和同时增加的排泄量是结构控制的热液循环系统中大气水快速入渗、加热和再循环的结果。.Um modelo hidrogeológico conceitual da fonte, vias de circulação e variação temporal de uma fonte termal de baixa entalpia em um ambiente de calcário fraturado é derivado de uma abordagem multidisciplinar. O poço de St. Gorman é uma fonte termal no centro-leste da Irlanda com um perfil de temperatura complexo e variável (máximo de 21.8°C). Os dados geofísicos de uma pesquisa áudio-magnetotelúrica (AMT) tridimensional (3D) são combinados com dados hidrogeológicos em intervalos de tempo e informações de uma análise hidroquimica publicada anteriormente, para investigar a operação deste intrigante sistema hidrotérmico. A análise hidroquimica e as medições em intervalos de tempo sugerem que as águas termais fluem de dentro dos calcários fraturados da Bacia Carbonifera de Dublin o tempo todo, mas exibem variabilidade na descarga e na temperatura. O modelo de resistividade elétrica 3D da subsuperfície revelou duas estruturas proeminentes: (1) um contato defeituoso alinhado a NO entre duas litologias de calcário; e (2) uma falha dissolucionalmente aumentada, alinhada a N, de provável idade Cenozóica. A intersecção dessas duas estruturas, que permitiu a carstificação da rocha calcária, criou condutos que facilitam a operação de circulação hidrotérmica relativamente profunda (profundidade estimada entre 240 e 1,000 m) dentro da sucessão de calcário da Bacia Dublin. Os resultados desse estudo suportam a hipótese de que a temperatura máxima e o aumento simultâneo da descarga observada no poço de St. Gorman a cada inverno é o resultado da rápida infiltração, aquecimento e recirculação de águas meteóricas dentro de um sistema de circulação hidrotérmica estruturalmente controlado.

[Schematic evolutionary model for the formation of different salt‐related structures discussed in this study highlighting their multiphase structural evolution. Seismic lines through the structures illustrated in the Southern, Central and Northern Slyne sub‐basins are shown in Figures 6, 7a and 8b respectively. NAIP, North Atlantic Igneous Province. , Abstract In contrast to much of the European Atlantic margin, the influence of salt on basin evolution has received little attention to date in the basins west of Ireland, despite salt being proven in several boreholes. Using an extensive seismic reflection database coupled with data from exploration wells and shallow boreholes, this study maps the distribution and composition of salt layers and investigates their role in the structural evolution of the Slyne and Erris basins offshore west of Ireland. Two salt‐prone intervals have been proven. The Upper Permian Zechstein Group is present throughout the Slyne and Erris basins, whereas the Upper Triassic Uilleann Halite Member is only developed in the Northern Slyne and Southern Erris sub‐basins. Both sedimentary units mechanically detach pre‐, post‐ and intra‐salt stratigraphy. Both salt layers underwent halokinesis during basin development, creating a variety of salt‐related structures. Salt pillows and salt rollers formed in the Zechstein Group, causing folding and rafting in the overlying Mesozoic section, driven by active faulting within the pre‐salt basement. Halokinesis in the Uilleann Halite Member caused thin‐skinned crestal collapse of the overlying Jurassic section above anticlines cored by Zechstein salt. Where both Triassic and Permian salt are present, unique structural geometries are formed when two stratigraphically discrete but kinematically linked halokinetic structures develop. The most common structural configuration consists of a Zechstein salt pillow and an Uilleann Halite salt wall separated by Lower Triassic sandstones. The fold axis of the salt pillow trends parallel to the strike of the salt wall. The results of this study provide a framework for the evolution of halokinetic structures in other basins on the Irish Atlantic margin, give a greater insight into the Permian and Triassic palaeogeography of the region and have more general implications for the evolution of salt‐related structures in rift basins with multiple stratigraphically discrete salt layers.]

Tourniquets have been used in the medical setting for centuries and have become the gold standard when preparing patients for surgery, particularly in orthopaedic surgery. Upper extremity tourniquet use improves intraoperative visibility and identification of anatomy. It also decreases blood loss intraoperatively and improves the safety of orthopaedic procedures. Despite the widespread use of tourniquets and differing methods of limb exsanguination, little research has been done quantifying its efficacy. The purpose of this study was to compare gravity exsanguination to Esmarch exsanguination of the upper extremity prior to tourniquet inflation in a large patient sample. A plethysmographic method based on water displacement served as a surrogate for the blood volume exsanguinated. Control measurements of water displacement were obtained from both upper extremities without tourniquet inflation. Water displacement was then measured with both gravity and Esmarch exsanguination techniques. Gender, handedness, height, weight, body mass index, and age were recorded for volunteers and used as covariates. Change in mean water displacement from control (un-exsanguinated) arm and gravity alone measurement was 37.2 ml. Change in mean water displacement between control arm and mean Esmarch measurement was 56.3 ml. Exsanguination using Esmarch compared to gravity alone resulted in a 51.2% increase in blood removal. Only age had a significant interaction effect for the Esmarch method. Analysis revealed that age accounted for 21.4% of all variance in blood exsanguinated using the Esmarch method when compared to the control group. The Esmarch technique was more efficacious for all demographics measured, but most efficacious in subjects who were older than 40 years. This data reaffirms that gravity exsanguination is more efficacious than no tourniquet use at all, and that the Esmarch technique is more efficacious than gravity. To our knowledge, this study is the most robust of its kind to critically and objectively compare upper extremity exsanguination methods and overall tourniquet use by age and supports the common practice of Esmarch exsanguination in orthopaedic extremity surgery.

Most petroleum reservoirs contain faults, and a key methodological challenge in full-field reservoir modeling is to include the effects of 3D sub-seismic fault zone structure within the 2D fault surfaces represented in commercially available simulators. To address this shortcoming, connectivity-based geometrical upscaling (GU) is introduced to include these fault zones implicitly in the upscaled reservoir model, and in this study, a comparison is made of the accuracy and flexibility of two different GU methods. The existing template-based geometrical upscaling (TBGU) method is compared to a newly developed flow-based geometrical upscaling (FBGU) method. In both methods, the faults and their associated single-phase fault rock properties are represented in the upscaled reservoir simulation model implicitly as neighbor and non-neighbor cell-to-cell connection transmissibilities, which are determined from 3D fault zone structures, but these transmissibilities are calculated in very different ways. Both approaches require a high-resolution reservoir model (i.e., truth model), containing 3D fault zone structure explicitly within the model geometry, which is then upscaled using the two methods to take into account the influences of the fault zone structure. The accuracy of both the upscaling methods is examined by comparing the flow behavior of the truth model with that of model versions upscaled using two different ways. The results of the two versions of upscaled models revealed significant differences and indicate that the FBGU technique is a much more accurate and flexible means of including structurally complex fault zone into low-resolution upscaled reservoir simulation models.

[Schematic illuration of tectonic deformations in the Porcupine Basin. , Abstract The Porcupine Basin is a large underexplored sedimentary basin located offshore west of Ireland within the structurally complex European North Atlantic Margin. The basin has evolved through multiple Jurassic–Recent phases of deformation and although the overall plate tectonic context of the margin is well‐documented, there are still uncertainties regarding the phases of tectonic activity, and their associated strain distribution and fault kinematics. Based on the analysis of large volumes of 2D and 3D seismic data from the Porcupine Basin, we provide an overview of the nature and origin of multiple fault systems, both tectonic and nontectonic, with links to regional tectonic events where possible. Three distinct basin‐wide phases of tectonically induced extensional faulting are recognized: (a) Late Jurassic N‐S to NE‐SW trending rift faults, (b) Late Cretaceous E‐W to ENE‐WSW trending normal faults and (c) Mid Eocene N‐S trending faults. The Jurassic faults were active over a period of 11.5 Myr between the Oxfordian and Kimmeridgian but with an intervening 4.5 Myr period of quiescence providing a two‐stage rift evolution. The Late Cretaceous faulting in the Porcupine Basin broadly correlates with extension in the Celtic Sea basins and is tentatively attributed to the rotational spreading of the Bay of Biscay in the south. The Mid Eocene phase of extension, which coincides with the onset of spreading between Europe and Greenland (Atlantic spreading), resulted in partial reactivation of the Jurassic faults. A series of non‐tectonic fault systems occur within specific stratigraphic intervals suggesting a compactional or gravitationally driven origin, including basinward dipping normal faults within a Palaeocene–early Eocene deltaic sequence, and multiple tiers of polygonal faults within Cretaceous, late Eocene and Neogene strata.]

To establish molecular magnetic resonance (MR) imaging instruments for in vivo characterization of the immune response to hepatic radiofrequency (RF) ablation using cell-specific immunoprobes.Seventy-two C57BL/6 wild-type mice underwent standardized hepatic RF ablation (70 °C for 5 minutes) to generate a coagulation area measuring 6-7 mm in diameter. CD68RF ablation-induced periablational infiltration (206.92 μm ± 12.2) of CD68Both SPION-enhanced T2

BACKGROUND: The immuno-metabolic interplay has gained interest for determining and targeting immunosuppressive tumor micro-environments that remain a barrier to current immuno-oncologic therapies in hepatocellular carcinoma. PURPOSE: To develop molecular MRI tools to reveal resistance mechanisms to immuno-oncologic therapies caused by the immuno-metabolic interplay in a translational liver cancer model. MATERIALS AND METHODS: A total of 21 VX2 liver tumor–bearing New Zealand white rabbits were used between October 2018 and February 2020. Rabbits were divided into three groups. Group A (n = 3) underwent intra-arterial infusion of gadolinium 160 ((160)Gd)–labeled anti–human leukocyte antigen–DR isotope (HLA-DR) antibodies to detect antigen-presenting immune cells. Group B (n = 3) received rhodamine-conjugated superparamagnetic iron oxide nanoparticles (SPIONs) intravenously to detect macrophages. These six rabbits underwent 3-T MRI, including T1- and T2-weighted imaging, before and 24 hours after contrast material administration. Group C (n = 15) underwent extracellular pH mapping with use of MR spectroscopy. Of those 15 rabbits, six underwent conventional transarterial chemoembolization (TACE), four underwent conventional TACE with extracellular pH– buffering bicarbonate, and five served as untreated controls. MRI signal intensity distribution was validated by using immunohistochemistry staining of HLA-DR and CD11b, Prussian blue iron staining, fluorescence microscopy of rhodamine, and imaging mass cytometry (IMC) of gadolinium. Statistical analysis included Mann-Whitney U and Kruskal-Wallis tests. RESULTS: T1-weighted MRI with (160)Gd-labeled antibodies revealed localized peritumoral ring enhancement, which corresponded to gadolinium distribution detected with IMC. T2-weighted MRI with SPIONs showed curvilinear signal intensity representing selective peritumoral deposition in macrophages. Extracellular pH–specific MR spectroscopy of untreated liver tumors showed acidosis (mean extracellular pH, 6.78 ± 0.09) compared with liver parenchyma (mean extracellular pH, 7.18 ± 0.03) (P = .008) and peritumoral immune cell exclusion. Normalization of tumor extracellular pH (mean, 6.96 ± 0.05; P = .02) using bicarbonate during TACE increased peri- and intratumoral immune cell infiltration (P = .002). CONCLUSION: MRI in a rabbit liver tumor model was used to visualize resistance mechanisms mediated by the immuno-metabolic interplay that inform susceptibility and response to immuno-oncologic therapies, providing a therapeutic strategy to restore immune permissiveness in liver cancer.

An acidic extracellular space is a hallmark of the tumor microenvironment. Acidosis has been postulated to promote the aggressive and invasive characteristics of tumors and also inhibit the therapeutic response, particularly in the context of novel immunotherapies. Therefore, methods to quantitatively measure the extracellular pH (pH

Abstract: The efficacy and tolerability of tubulin binding agents are hampered by their low specificity for cancer cells like most clinically used anticancer agents. To improve specificity, tubulin binding agents have been covalently conjugated to agents that target cancer cells to give actively targeted drug conjugates. These conjugates are designed to increase uptake of the drug by cancer cells while having limited uptake by normal cells, thereby improving efficacy and tolerability. Approaches used include an attachment to small molecules, polysaccharides, peptides, proteins, and antibodies that exploit the overexpression of receptors for these substances. Antibody targeted strategies have been the most successful to date, with six such examples having gained clinical approval. Many other conjugate types, especially those targeting the folate receptor, have shown promising efficacy and toxicity profiles in pre-clinical models and in early-stage clinical studies. Presented herein is a discussion of the success or otherwise of the recent strategies used to form these actively targeted conjugates.

The goal of this study was to investigate the effects of TACE using Lipiodol, Oncozene™ drug-eluting embolics (DEEs), or LUMI™-DEEs alone, or combined with bicarbonate on the metabolic and immunological tumor microenvironment in a rabbit VX2 tumor model. VX2 liver tumor-bearing rabbits were assigned to five groups. MRI and extracellular pH (pHe) mapping using Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) were performed before and after intra-arterial therapy with conventional TACE (cTACE), DEE-TACE with Idarubicin-eluting Oncozene™-DEEs, or Doxorubicin-eluting LUMI™-DEEs, each with or without prior bicarbonate infusion, and in untreated rabbits or treated with intra-arterial bicarbonate only. Imaging results were validated with immunohistochemistry (IHC) staining of cell viability (PCNA, TUNEL) and immune response (HLA-DR, CD3). Statistical analysis was performed using Mann–Whitney U test. pHe mapping revealed that combining cTACE with prior bicarbonate infusion significantly increased tumor pHe compared to control (p = 0.0175) and cTACE alone (p = 0.0025). IHC staining revealed peritumoral accumulation of HLA-DR+ antigen-presenting cells and CD3 + T-lymphocytes in controls. cTACE-treated tumors showed reduced immune infiltration, which was restored through combination with bicarbonate. DEE-TACE with Oncozene™-DEEs induced moderate intratumoral and marked peritumoral infiltration, which was slightly reduced with bicarbonate. Addition of bicarbonate prior to LUMI™-beads enhanced peritumoral immune cell infiltration compared to LUMI™-beads alone and resulted in the strongest intratumoral immune cell infiltration across all treated groups. The choice of chemoembolic regimen for TACE strongly affects post-treatment TME pHe and the ability of immune cells to accumulate and infiltrate the tumor tissue. • Combining conventional transarterial chemotherapy with prior bicarbonate infusion increases the pHe towards a more physiological value (p = 0.0025). • Peritumoral infiltration and intratumoral accumulation patterns of antigen-presenting cells and T-lymphocytes after transarterial chemotherapy were dependent on the choice of the chemoembolic regimen. • Combination of intra-arterial treatment with Doxorubicin-eluting LUMI™-beads and bicarbonate infusion resulted in the strongest intratumoral presence of immune cells (positivity index of 0.47 for HLADR+-cells and 0.62 for CD3+-cells).

Faults are important structures in the formation of many mineral deposits, often acting as conduits for ore-forming fluids and sometimes providing, or generating, the bounding structures to associated mineralizing sites. Using 3-D analysis and modeling of the Lisheen and Silvermines deposits within the Irish ore field, we investigate the geometry of normal fault systems and their implications on the origin and nature of associated deposits. These Irish-type deposits are carbonate hosted and developed within the hanging walls of normal faults arising from an Early Carboniferous episode of north-south rifting, with relatively limited amounts of later deformation. Structural analysis of high-quality mine datasets indicates that fault segmentation is ubiquitous with left-stepping segments arising from north-south stretching developed above generally ENE-NE-trending fault arrays, which are subparallel to older Caledonian penetrative fabrics and structure within underlying Silurian and Ordovician rocks. Fault segments occur on different scales and have a profound impact on structural evolution, with larger scale segments and intervening relay ramps defining distinct orebodies within deposits and smaller scale segments and relays potentially providing paths for upfault fluid flow. The difference in behavior is attributed to the integrity of associated relay ramps where intact ramps represent orebody-bounding structures, and smaller breached ramps provide enhanced associated hydraulic properties and act as vertical conduits. Hanging-wall deformation along the rheological boundary between host-rock limestones and underlying shales has an important control on the localization of earlier dolomitization and/or brecciation and later mineralization adjacent to this contact, and on the migration pathways for basinal brines and mineralizing fluids. European Commission Horizon 2020 European Commission - Seventh Framework Programme (FP7) Science Foundation Ireland European Regional Development Fund

Plant-derived polyphenols are known to have promising biological activities including antioxidant and antityrosinase and may be a potential candidate for anti-dermatoheliotic remedy. The present study was performed to investigate the polyphenolic contents of Mimosa pudica (MP) seed extract and its anti-dermatoheliotic potential using non-invasive biophysical techniques after developing a stable topical emulgel formulation. Moreover, its in-vitro cytotoxicity was also evaluated using normal Human keratinocytes (HaCat cells) to rule out any cellular incompatibility. The results revealed that MP seed extract, constituted with a number of polyphenolic compounds, has very good antioxidant and anti-tyrosinase potential. There were significant positive effects (p ≤ 0.05) invoked by its topical emulgel formulation on various dermatoheliotic associated skin parameters like erythema, melanin, elasticity, hydration, and sebum as compared to placebo. In the meantime, it was also found to be biocompatible and did not show any effect on HaCat cell viability and structure. In conclusion, the topical emulgel preparation loaded with MP seed extract could be a great strategy to deal with dematoheliosis.

Carboniferous (Mississippian) limestones of the Burren are cross-cut by sub-vertical veins, from 1µm up to 50cm thick, defining a strongly clustered and scale-indepen-dent system in which predominantly N-S veins are transected by longer NNE-trending veins. Vein infills mainly comprise of calcite, but with subordinate amounts of quartz, sulphide (mainly galena and sphalerite) and fluorite also occurring, particularly in the south-central part of the area. Thinner and shorter veins are planar and discontinuous in plan view, sometimes forming en-echelon arrays, with thicker veins forming better connected and more complex structures which extend for several kilometres across the Burren region. Veins with ‘exotic’ infills are generally both longer and thicker, and they appear to be spatially associated with, or up to 5km to the north of, a 5km wide zone of ENE-trending Variscan monoclinal folding. Individual veins are vertically persistent, and the same structures are seen throughout the exposed ca 1200m thick Carboniferous sequence, from Tournaisian limestones through to Serpukhovian-Bashkirian siliciclastics. The veins are mainly extensional, sometimes with a component of sinistral displacement particularly on NNE-trending veins, displaying fibrous growth through to hydraulic fracturing and brecciation. Their formation is attributed to the valving of overpressured fluids within Mississippian basins during N-S Variscan compression. Pb isotope analysis supports a model in which sulphide infills are scavenged from underlying basement rocks or hydrothermal Zn-Pb mineralisation during the tectonic inversion of post-rift sequences overlying Lower Carboniferous normal faults. Environmental Protection Agency European Commission - European Regional Development Fund Science Foundation Ireland Geological Survey Ireland/DCCAE Postdoctoral Fellowship Programme

Overlapping opposed-dipping normal faults can have complementary displacement distributions, indicating transfer of displacement between them in the same way as at relay zones between faults with the same dip direction. We constrain the mechanism by which displacement is transferred between opposed-dipping faults by examining the geometries of faulted horizons and fault throw distributions at these conjugate relay zones. Structure contour maps of horizons offset by overlapping opposed-dipping faults from different extensional settings display a consistent pattern. Above the line of intersection between the conjugate faults the deformed horizon is flat between converging faults and displacement transfer is reflected in changes in footwall elevation. Below the line of fault intersection the mutual footwall is flat and elevation changes occur in the hanging walls of the divergent faults. These elevation changes can be explained as a simple superposition of the deformation fields of two faults that have retarded lateral propagation due to the presence of the other synchronous fault, irrespective of whether the two faults actually intersect. The observed patterns of horizon elevation strongly resemble those seen at boundaries between adjacent basin-scale half-graben of opposed polarity.

A paucity of displacement markers can make constraining the kinematics and interaction of regional-scale strike-slip faults difficult. In this study, a high-resolution aeromagnetic survey allows quantitative analysis of kilometre-scale Paleogene faulting in the north of Ireland. Mapping offset dykes and igneous centres reveals the presence of two orientations of Cenozoic strike-slip faults attributed to broadly N-S Alpine shortening arising from the convergence of Africa and Europe. Reactivated NE-SW striking faults accommodated up to 2.3 km of sinistral displacement mainly during the Paleocene. Following tectonic quiescence, up to 2.5 km of Oligocene-aged dextral movement was accommodated on newly-formed NNW-SSE striking faults. Displacement analysis suggests that the faults were kinematically linked and experienced a switch in polarity of the predominantly active fault orientation during the Paleogene, forming an apparent conjugate system with asymmetric displacement distributions. The switch in fault polarity is attributed to a rotation in the regional maximum horizontal stress orientation and the locus of deformation moving from pre-existing reactivated structures to newly formed faults. The analysis also illustrates that, despite low strain rates, the interaction of the principal components of the fault system controlled the formation of sedimentary basins and defined the present-day geography of the region, far from an active plate boundary.

Tourniquets have been used in the medical setting for centuries and have become the gold standard when preparing patients for surgery, particularly in orthopaedic surgery. Upper extremity tourniquet use improves intraoperative visibility and identification of anatomy. It also decreases blood loss intraoperatively and improves the safety of orthopaedic procedures. Despite the widespread use of tourniquets and differing methods of limb exsanguination, little research has been done quantifying its efficacy. The purpose of this study was to compare gravity exsanguination to Esmarch exsanguination of the upper extremity prior to tourniquet inflation in a large patient sample. A plethysmographic method based on water displacement served as a surrogate for the blood volume exsanguinated. Control measurements of water displacement were obtained from both upper extremities without tourniquet inflation. Water displacement was then measured with both gravity and Esmarch exsanguination techniques. Gender, handedness, height, weight, body mass index, and age were recorded for volunteers and used as covariates. Change in mean water displacement from control (un-exsanguinated) arm and gravity alone measurement was 37.2 ml. Change in mean water displacement between control arm and mean Esmarch measurement was 56.3 ml. Exsanguination using Esmarch compared to gravity alone resulted in a 51.2% increase in blood removal. Only age had a significant interaction effect for the Esmarch method. Analysis revealed that age accounted for 21.4% of all variance in blood exsanguinated using the Esmarch method when compared to the control group. The Esmarch technique was more efficacious for all demographics measured, but most efficacious in subjects who were older than 40 years. This data reaffirms that gravity exsanguination is more efficacious than no tourniquet use at all, and that the Esmarch technique is more efficacious than gravity. To our knowledge, this study is the most robust of its kind to critically and objectively compare upper extremity exsanguination methods and overall tourniquet use by age and supports the common practice of Esmarch exsanguination in orthopaedic extremity surgery.

Under normal conditions, high sodium (Na+) in extracellular (Na+e) and blood (Na+b) compartments and low Na+ in intracellular milieu (Na+i) produce strong transmembrane (ΔNa+mem) and weak transendothelial (ΔNa+end) gradients respectively, and these manifest the cell membrane potential (Vm) as well as blood–brain barrier (BBB) integrity. We developed a sodium (23Na) magnetic resonance spectroscopic imaging (MRSI) method using an intravenously-administered paramagnetic polyanionic agent to measure ΔNa+mem and ΔNa+end. In vitro 23Na-MRSI established that the 23Na signal is intensely shifted by the agent compared to other biological factors (e.g., pH and temperature). In vivo 23Na-MRSI showed Na+i remained unshifted and Na+b was more shifted than Na+e, and these together revealed weakened ΔNa+mem and enhanced ΔNa+end in rat gliomas (vs. normal tissue). Compared to normal tissue, RG2 and U87 tumors maintained weakened ΔNa+mem (i.e., depolarized Vm) implying an aggressive state for proliferation, whereas RG2 tumors displayed elevated ∆Na+end suggesting altered BBB integrity. We anticipate that 23Na-MRSI will allow biomedical explorations of perturbed Na+ homeostasis in vivo.

Normal faults are often complex three-dimensional structures comprising multiple sub-parallel segments separated by intact or breached relay zones. In this study we outline geometrical characterisations capturing this 3D complexity and providing a semi-quantitative basis for the comparison of faults and for defining the factors controlling their geometrical evolution. Relay zones are classified according to whether they step in the strike or dip direction and whether the relay zone-bounding fault segments are unconnected in 3D or bifurcate from a single surface. Complex fault surface geometry is then described in terms of the relative numbers of different types of relay zones to allow comparison of fault geometry between different faults and different geological settings. A large database of 87 fault arrays compiled primarily from mapping 3D seismic reflection surveys and classified according to this scheme, reveals the diversity of 3D fault geometry. Analysis demonstrates that mapped fault geometries depend on geological controls, primarily the heterogeneity of the faulted sequence and the presence of a pre-existing structure. For example, relay zones with an upward bifurcating geometry are prevalent in faults that reactivate deeper structures, whereas the formation of laterally bifurcating relays is promoted by heterogeneous mechanical stratigraphy. In addition, mapped segmentation depends on resolution limits and biases in fault mapping from seismic data. In particular, the results suggest that the proportion of bifurcating relay zones increases as data resolution increases. Overall, where a significant number of relay zones are mapped on a single fault, a wide variety of relay zone geometries occurs, demonstrating that individual faults can comprise segments that are both bifurcating and unconnected in three dimensions. Models for the geometrical evolution of fault arrays must therefore account for the full range of relay zone geometries that appears to be a characteristic of all faults.

Inhaled corticosteroid therapy (ICS) is increasingly reported as a cause of adrenal insufficiency (AI). The exact prevalence is difficult to ascertain and may be confounded by exposure to oral glucocorticoids (OCS) and potential selection bias. This study aims to establish the relative contribution of OCS and ICS exposure to adrenal suppression in a severe asthma cohort. Methods Serum cortisol samples (pre 11am) were collected from participants at their last visit in the INCA SUN RCT and analysed using the Roche Elecsys Cortisol II assay. Participants were stratified into three groups based on serum cortisol concentration (suppressed cortisol 315 nmol/l which would predict a passed SST). OCS cumulative exposure was recorded during the study and ICS cumulative exposure was calculated using each patients’ mean ICS adherence data obtained from their INCA device, an electronic monitoring device which accounts for adherence and inhaler technique. Results 65 participants were included for analysis. 20% (13/65) of participants had a morning cortisol Serum cortisol was strongly predicted by cumulative glucocorticoid exposure. Linear regression of serum cortisol versus mean daily ICS exposure showed a reduction in serum cortisol of -120 nmol/L [-224, -22] per milligram increase in fluticasone propionate (FP) exposure (p=0.02). When adjusted for cumulative OCS exposure, this relationship remained significant, with an effect size of -90 nmol/L [ -13, -175]. Conclusion At least 20% of patients with difficult to treat asthma may have undiagnosed AI. While OCS exposure is strongly associated with serum cortisol, our analysis shows that there is also a strong association between cumulative ICS exposure and the risk of AI.

The design, implementation and evaluation of a year 1 pharmacy-integrated learning component, using the World Health Organisation’s (WHO) analgesic ladder as a scaffold for case-based learning, is described. A novel aspect of the integrated component is the mapping of the cases to the national Core Competency Framework (CCF) for Pharmacists in Ireland and to the school’s own cross-cutting curricular integration themes. The integrated cases were student led and delivered through peer-to-peer teaching for 68 first-year pharmacy students. The integrated cases mapped strongly to three of the CCF’s domains, namely, personal skills, organisation and management skills and supply of medicines. With regard to the school’s curricular integrative themes, the cases mapped strongly to the curricular integration themes of professionalism and communications; medicines sourcing, production and use; and safe and rational use of medicines. Highlights from an anonymous online student survey were the recognition by students of the importance of core science knowledge for practice, the enabling of integrated learning and the suitability of the integrated component for entry-level. While a majority of students were found to favour individual work over group work, future iterations will need to consider a greater degree of group work with a view to reducing the volume of content and time required to complete the cases.

Nursing home residents experience death and injury at a disproportionately higher rate than other populations during and after a disaster. This paper addresses the complex chronic conditions of vulnerable residents that will become even more challenging due to compounding effects from continued disasters and rapid population aging. In 2016, the Centers for Medicare and Medicaid Services (CMS) established national emergency preparedness requirements for long-term care (LTC) and skilled nursing (SN) facilities. The problems facing nursing facilities created by an increasing population to serve, present a challenge to meeting the highest level of requirements and responsibilities for healthcare preparedness. This paper argues that nursing facility personnel are required to participate in an unfamiliar culture of operational processes, using terminology foreign to their profession, in an environment requiring planning and decision-making skills using organisational concepts they most likely have never experienced. Furthermore, unlike hospitals, LTC and SN facility staff have not had extensive access to standardised training to meet the current requirements. The paper concludes that this environment adversely affects emergency managers and unnecessarily increases their planning and operational burden.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The neural circuits responsible for animal behavior remain largely unknown. We summarize new methods and present the circuitry of a large fraction of the brain of the fruit fly Drosophila melanogaster. Improved methods include new procedures to prepare, image, align, segment, find synapses in, and proofread such large data sets. We define cell types, refine computational compartments, and provide an exhaustive atlas of cell examples and types, many of them novel. We provide detailed circuits consisting of neurons and their chemical synapses for most of the central brain. We make the data public and simplify access, reducing the effort needed to answer circuit questions, and provide procedures linking the neurons defined by our analysis with genetic reagents. Biologically, we examine distributions of connection strengths, neural motifs on different scales, electrical consequences of compartmentalization, and evidence that maximizing packing density is an important criterion in the evolution of the fly’s brain., eLife digest Animal brains of all sizes, from the smallest to the largest, work in broadly similar ways. Studying the brain of any one animal in depth can thus reveal the general principles behind the workings of all brains. The fruit fly Drosophila is a popular choice for such research. With about 100,000 neurons – compared to some 86 billion in humans – the fly brain is small enough to study at the level of individual cells. But it nevertheless supports a range of complex behaviors, including navigation, courtship and learning. Thanks to decades of research, scientists now have a good understanding of which parts of the fruit fly brain support particular behaviors. But exactly how they do this is often unclear. This is because previous studies showing the connections between cells only covered small areas of the brain. This is like trying to understand a novel when all you can see is a few isolated paragraphs. To solve this problem, Scheffer, Xu, Januszewski, Lu, Takemura, Hayworth, Huang, Shinomiya et al. prepared the first complete map of the entire central region of the fruit fly brain. The central brain consists of approximately 25,000 neurons and around 20 million connections. To prepare the map – or connectome – the brain was cut into very thin 8nm slices and photographed with an electron microscope. A three-dimensional map of the neurons and connections in the brain was then reconstructed from these images using machine learning algorithms. Finally, Scheffer et al. used the new connectome to obtain further insights into the circuits that support specific fruit fly behaviors. The central brain connectome is freely available online for anyone to access. When used in combination with existing methods, the map will make it easier to understand how the fly brain works, and how and why it can fail to work correctly. Many of these findings will likely apply to larger brains, including our own. In the long run, studying the fly connectome may therefore lead to a better understanding of the human brain and its disorders. Performing a similar analysis on the brain of a small mammal, by scaling up the methods here, will be a likely next step along this path.

[Abstract The Celtic Sea basins lie on the continental shelf between Ireland and northwest France and consist of a series of ENE–WSW trending elongate basins that extend from St George’s Channel Basin in the east to the Fastnet Basin in the west. The basins, which contain Triassic to Neogene stratigraphic sequences, evolved through a complex geological history that includes multiple Mesozoic rift stages and later Cenozoic inversion. The Mizen Basin represents the NW termination of the Celtic Sea basins and consists of two NE–SW‐trending half‐grabens developed as a result of the reactivation of Palaeozoic (Caledonian, Lower Carboniferous and Variscan) faults. The faults bounding the Mizen Basin were active as normal faults from Early Triassic to Late Cretaceous times. Most of the fault displacement took place during Berriasian to Hauterivian (Early Cretaceous) times, with a NW–SE direction of extension. A later phase of Aptian to Cenomanian (Early to Late Cretaceous) N–S‐oriented extension gave rise to E–W‐striking minor normal faults and reactivation of the pre‐existing basin bounding faults that propagated upwards as left‐stepping arrays of segmented normal faults. In common with most of the Celtic Sea basins, the Mizen Basin experienced a period of major erosion, attributed to tectonic uplift, during the Paleocene. Approximately N–S Alpine regional compression‐causing basin inversion is dated as Middle Eocene to Miocene by a well‐preserved syn‐inversion stratigraphy. Reverse reactivation of the basin bounding faults was broadly synchronous with the formation of a set of near‐orthogonal NW–SE dextral strike‐slip faults so that compression was partitioned onto two fault sets, the geometrical configuration of which is partly inherited from Palaeozoic basement structure. The segmented character of the fault forming the southern boundary of the Mizen Basin was preserved during Alpine inversion so that Cenozoic reverse displacement distribution on syn‐inversion horizons mirrors the earlier extensional displacements. Segmentation of normal faults therefore controls the geometry and location of inversion structures, including inversion anticlines and the back rotation of earlier relay ramps., Reverse displacements during inversion mirror normal displacements during extension. Inversion occurred by coeval reverse reactivation of normal faults and dextral strike‐slip faulting. The throw profiles are stepped where they intersect the larger strike‐slip faults increases in throw across the branchpoints with the dextral strike‐slip faults. ]

The neural circuits responsible for animal behavior remain largely unknown. We summarize new methods and present the circuitry of a large fraction of the brain of the fruit fly Drosophila melanogaster. Improved methods include new procedures to prepare, image, align, segment, find synapses in, and proofread such large data sets. We define cell types, refine computational compartments, and provide an exhaustive atlas of cell examples and types, many of them novel. We provide detailed circuits consisting of neurons and their chemical synapses for most of the central brain. We make the data public and simplify access, reducing the effort needed to answer circuit questions, and provide procedures linking the neurons defined by our analysis with genetic reagents. Biologically, we examine distributions of connection strengths, neural motifs on different scales, electrical consequences of compartmentalization, and evidence that maximizing packing density is an important criterion in the evolution of the fly’s brain.

This study uses a combination of 2D and 3D seismic reflection surveys coupled with borehole data from the Irish Atlantic margin to map the distribution of salt in the Slyne and Erris basins and understand its influence on basin development throughout the Mesozoic.The north-western European Atlantic margin is populated by a framework of rift basins stretching from the Barents Sea offshore northern Norway to the south of Portugal. Several of these basins contain significant quantities of salt, which plays an important role in basin development and structural evolution. While salt is present on the Irish Atlantic margin, its distribution and role in basin development is poorly understood. The Slyne and Erris basins, off the northern coast of Ireland, contain two proven layers of salt; the Upper Permian Zechstein Group and the Upper Triassic Uilleann Halite Member of the Currach Formation.Where present in their salt-dominated forms, both layers act as décollements, mechanically detaching pre-, intra- and post-salt stratigraphy. The Zechstein Group is present throughout the Slyne and Erris basins, while the Uilleann Halite Member is only developed in the northern Slyne Basin and the southern Erris Basin. Both salt layers have undergone significant halokinesis during basin development, and their original thicknesses are unclear. This halokinesis has played a significant role in the formation of hydrocarbon traps in these basins: the Zechstein Group forms salt pillows and salt rollers, causing folding and rafting in the overlying Mesozoic section, driven by active faulting in the pre-salt Palaeozoic basement. The Uilleann Halite Member caused thin-skinned crestal collapse and delamination of the overlying Jurassic section above anticlines cored by Zechstein salt. Both layers of salt play a key role in the development of the Corrib gas field and are responsible for trap formation in the Corrib North and Bandon discoveries. Understanding the genesis of these salt-related structures in a multi-layered salt system will provide insight into future exploration activities in salt-prone basins offshore Ireland, as well as their suitability for storage of sequestered CO2.ICRAG is funded in part by a research grant from Science Foundation Ireland (SFI) under Grant Number 13/RC/2092 and is co-funded under the European Regional Development Fund and by PIPCO RSG and its member companies.

The lack of an unambiguous method for determining the propagation direction of slip events on faults over significant time periods limits our understanding of the long-term stability of fault slip propagation directions. A geological means for determining the propagation direction of slip events during the growth of faults is provided by mutually cross-cutting faults and bed-parallel slip-surfaces in the Ptolemais Basin, northern Greece.In the Kardia lignite mine, Ptolemais Basin, bed-parallel slip surfaces intermittently offset the Quaternary faults as they grew to form discontinuities on otherwise continuous fault surfaces. Subsequent fault slip increments bypassed these discontinuities to re-establish a continuous fault trace and leave an associated ‘dead’ splay. The geometry and displacement distributions at these fault/bed-parallel slip intersections record the fault displacement at the time of bed-parallel slip and whether the next fault slip increment had an upwards or downwards component to its local propagation vector.A database (N = 88) of slip propagation directions and fault throws was derived from continuous mapping of mine faces during lignite extraction over an eight year period. The data demonstrate a clear relationship between slip propagation direction and the accumulation of fault displacement on individual faults. During the early stages of fault growth, slip events propagated almost exclusively upwards through the mined sequence, but later stages of growth are marked by slip events showing both upward and downward components of propagation. The data therefore demonstrate that the location of the point of initiation of fault slip events on these Quaternary faults varied over the fault surfaces as the faults grew.The emergence of systematic results from our analyses suggests that cross-cutting relationships between other synchronously active structures (e.g. conjugate faults) can provide a robust means for determining the propagation directions of slip events on ancient faults at outcrop.

The hyper-extended Porcupine Basin, offshore southwest Ireland, is a component of the Eastern North Atlantic rifted continental margin. The basin developed following multiple rifting phases with different extension directions between the Late-Palaeozoic and the Cenozoic. The present-day north-south trend of the Porcupine Basin developed during the main Middle-Jurassic to Lower-Cretaceous rifting phase, which is interpreted to have overprinted earlier extension directions. In this study, we outline the tectono-stratigraphic architecture and the kinematics of the Porcupine Basin derived from seismic interpretation and fault analysis of multiple 2D and 3D seismic datasets.Our ongoing work identifies different fault networks with distinctive orientations and ages, confirming multiple rifting phases of the basin. The older faults identified strike NE/SW and offset the top of the Jurassic basement and the oldest syn-tectonic sequences. The younger faults strike N/S, offset the whole syn-tectonic stratigraphic sequence and bound the present-day tilted blocks of thinned continental crust. Interactions between these two main generations of faults created strong lateral variability in the geometry of the fault-bounded blocks. In addition, our interpretations highlight strong segmentation along the axis of the basin, evidenced by changes in the structural architecture of the faults along the flanks of the basin, and by rapid changes in the depth to the Jurassic basement from one segment to another. This segmentation occurs across several lineaments that are orthogonal to the main N-S direction of the tilted blocks observed along the flanks of the basin, and that are also observed in the central parts of the basin with gravity data and by the compartmentalisation of sedimentary depocenters. We interpret these lineaments as transfer zones that can be related to the kinematics of the basin. These zones may have accommodated either temporal or spatial changes in the directions of extension, or a stepped variation in E-W extension along the axis of the basin.Our results help to better understand the controls on the geometry and kinematics of fault systems within the Porcupine Basin, and to better evaluate the structural evolution of the Porcupine Basin and its significance in the broader context of the North Atlantic rifting.

Normal faults are often complex three dimensional structures comprising multiple sub-parallel segments separated by intervening relay zones. In this study we outline geometrical characterisations capturing this 3D complexity and providing a semi-quantitative basis for the comparison of faults and for defining the factors controlling their geometrical evolution.Individual relay zones can be assigned to one of four types according to their form (i.e. whether the bounding segments are unconnected in 3D or merge into a single surface) and their orientation (i.e. whether they are slip-parallel or slip-perpendicular). From the detailed analysis of 84 fault arrays mapped from 3D seismic reflection surveys (including 63 from our mapping of 8 different study areas and 21 derived from the literature), we show that the 3D geometry of fault arrays can be quantitatively defined on the basis of the relative numbers of these types of relay zones.Detailed mapping of fault zones indicates that whilst they can individually contain all four types of relay zone, their relative proportions varies between different study areas. Differences in the proportions of relay zone types are attributed to two primary controls, the mechanical heterogeneity of the faulted sequence and the presence of basement structure. For example, relay zones with an upward bifurcating geometry are prevalent in faults that reactivate deeper structures, whereas the formation of laterally bifurcating relays is promoted by heterogeneous mechanical stratigraphy. Fault arrays in the literature generally do not contain the full range of possible relay zone type but tend to comprise either all bifurcating relay zones or all unconnected relay zones. These end-member fault geometries have led to contrasting conceptual models for the growth of faults. The mapping conducted here suggests that the proportion of bifurcating relay zones increases as data resolution increases and that fault surface bifurcation is ubiquitous. Models for the geometrical evolution of fault arrays must account for the full range of relay zone geometries that appears to be a characteristic of all faults.

The neural circuits responsible for behavior remain largely unknown. Previous efforts have reconstructed the complete circuits of small animals, with hundreds of neurons, and selected circuits for larger animals. Here we (the FlyEM project at Janelia and collaborators at Google) summarize new methods and present the complete circuitry of a large fraction of the brain of a much more complex animal, the fruit fly Drosophila melanogaster. Improved methods include new procedures to prepare, image, align, segment, find synapses, and proofread such large data sets; new methods that define cell types based on connectivity in addition to morphology; and new methods to simplify access to a large and evolving data set. From the resulting data we derive a better definition of computational compartments and their connections; an exhaustive atlas of cell examples and types, many of them novel; detailed circuits for most of the central brain; and exploration of the statistics and structure of different brain compartments, and the brain as a whole. We make the data public, with a web site and resources specifically designed to make it easy to explore, for all levels of expertise from the expert to the merely curious. The public availability of these data, and the simplified means to access it, dramatically reduces the effort needed to answer typical circuit questions, such as the identity of upstream and downstream neural partners, the circuitry of brain regions, and to link the neurons defined by our analysis with genetic reagents that can be used to study their functions.Note: In the next few weeks, we will release a series of papers with more involved discussions. One paper will detail the hemibrain reconstruction with more extensive analysis and interpretation made possible by this dense connectome. Another paper will explore the central complex, a brain region involved in navigation, motor control, and sleep. A final paper will present insights from the mushroom body, a center of multimodal associative learning in the fly brain.